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ANILINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Aniline is the simplest aromatic amine and is an irritant and mild sensitizer. It can induce methemoglobinemia, Heinz-body hemolytic anemia, and associated symptoms of oxygen deprivation. It has been splenotoxic and cardiotoxic in experimental animals (Khan et al, 1998).

Specific Substances

    1) Anilin
    2) Anilina
    3) Aniline oil
    4) Anyvim
    5) Benzenamine
    6) Benzene, amino-
    7) Benzidam
    8) Blue Oil
    9) C.I. 76000
    10) C.I. Oxidation Base 1
    11) Cyanol
    12) Hiule d'aniline
    13) Krystallin
    14) Kyanol
    15) Phenylamine
    16) Molecular Formula: C6-H7-N
    17) CAS 62-53-3
    18) ANALINE (MISSPELLING FOR ANILINE)
    1.2.1) MOLECULAR FORMULA
    1) C6-H7-N

Available Forms Sources

    A) FORMS
    1) It is a clear, oily liquid, which turns brown with exposure to air and light. It has a distinctive, amine-like, or musty, fishy odor and an acrid taste. It is heavier than water and its vapors are heavier than air; the fumes may be poisonous if inhaled. It is combustible, and volatile with steam (AAR, 2000; Budavari, 2000; Lewis, 1998).
    2) Aniline is available in commercial grade and chemically pure. The commercial grade contains 99.9% (minimum) aniline, with 0.1% (maximum) moisture and 0.0002% (maximum) nitrobenzene (HSDB , 2001).
    B) SOURCES
    1) Aniline is produced by the catalytic vapor-phase reduction of nitrobenzene with hydrogen, the reduction of nitrobenzene with iron filings using hydrochloric acid as the catalyst, the catalytic reaction of chlorobenzene and aqueous ammonia, and by the ammonolysis of phenol in Japan (Ashford, 1994; Lewis, 1997a).
    C) USES
    1) Aniline is used to manufacture other chemicals such as dyes, photographic and agricultural chemicals (AAR, 2000).
    2) Aniline is also the parent substance for the synthesis of rubber accelerators and antioxidants, drugs, isocyanates, herbicides, and fungicides (ACGIH, 1991).
    3) Aniline is a common ingredient of certain household products including shoe polish, paints, varnishes and inks. It is also used to manufacture perfumes (Lewis, 1998; OHM/TADS, 2001).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) WITH POISONING/EXPOSURE
    1) Aniline is a skin and eye irritant and a mild dermal sensitizer. It is rapidly absorbed by all routes and induces methemoglobinemia. Symptoms of methemoglobinemia include cyanosis, headache, dizziness, weakness, lethargy, loss of coordination, dyspnea, coma, and death. A Heinz-body hemolytic crisis may follow the development of methemoglobinemia by 2 to 7 days. Heart, liver, and kidney effects may be secondary to hemolysis.
    a) Additional signs and symptoms of exposure may include photophobia, visual disturbances, sluggish pupillary reaction, tinnitus, speech disturbances, anorexia, nausea, colicky pain, muscle pain, faintness, paresthesias, tremor, seizures, cardiac dysrhythmias, and heart block. Urinary signs and symptoms may include painful micturition, hemoglobinuria, methemoglobinuria, hematuria, oliguria, and renal insufficiency.
    0.2.3) VITAL SIGNS
    A) WITH POISONING/EXPOSURE
    1) Acute poisoning may cause tachycardia and tachypnea.
    0.2.4) HEENT
    A) WITH POISONING/EXPOSURE
    1) Cyanosis may occur. Corneal damage, discoloration, and mild to severe irritation of the eyes have been noted.
    0.2.5) CARDIOVASCULAR
    A) WITH POISONING/EXPOSURE
    1) Cardiovascular collapse and dysrhythmias have been noted. Subendocardial necrosis has been seen in exposed experimental animals but has not been reported in humans.
    0.2.6) RESPIRATORY
    A) WITH POISONING/EXPOSURE
    1) Signs of hypoxia may be present.
    2) Pulmonary infiltrates, respiratory failure, and pulmonary hypertension have been attributed to exposure to rapeseed oil denatured in part with aniline as part of the "toxic oil syndrome."
    0.2.7) NEUROLOGIC
    A) WITH POISONING/EXPOSURE
    1) Severe headache, CNS disturbances, and tremor may occur. CNS depression may be a result of aniline-induced methemoglobinemia.
    0.2.8) GASTROINTESTINAL
    A) WITH POISONING/EXPOSURE
    1) Nausea and vomiting can occur.
    0.2.9) HEPATIC
    A) WITH POISONING/EXPOSURE
    1) Liver damage and jaundice may occur in patients with aniline poisoning.
    2) Aniline-treated rats had slightly decreased hepatic alkaline phosphate content and normal amino acids.
    0.2.10) GENITOURINARY
    A) Hematuria, gynecological disorders, and nephrosis have been noted.
    0.2.13) HEMATOLOGIC
    A) WITH POISONING/EXPOSURE
    1) Methemoglobinemia and hemolytic anemia may occur in acute aniline poisoning. Alcohol interaction may intensify the activity in inducing methemoglobinemia.
    0.2.14) DERMATOLOGIC
    A) WITH POISONING/EXPOSURE
    1) Dermal absorption is rapid. Cyanosis, moderate skin irritation and sensitization, and dermatitis have been noted.
    0.2.16) ENDOCRINE
    A) Adrenal effects have been found in experimental animals.
    0.2.19) IMMUNOLOGIC
    A) WITH POISONING/EXPOSURE
    1) Aniline poisoning can cause allergic contact dermatitis.
    0.2.20) REPRODUCTIVE
    A) A high incidence of gynecological disorders and excess frequency of spontaneous abortions have been noted. The fetal liver can n-oxygenate aniline to form phenylhydroxylamine. Fetal effects include higher levels of methemoglobin than those found in the mother. Fetal poisoning may occur.
    B) At the time of this review, no data were available to assess the potential effects of exposure to aniline during lactation.
    C) No information about possible male reproductive effects was found in available references at the time of this review
    0.2.22) OTHER
    A) WITH POISONING/EXPOSURE
    1) Predisposing medical and exposure conditions may exist. Refer to main CLINICAL EFFECTS section for more information. Toxic oil syndrome (TOS) occurred in Spain in 1981 from exposure to rapeseed oil contaminated with 2% aniline.

Laboratory Monitoring

    A) Monitor methemoglobin levels, hemoglobin, hematocrit, and plasma free hemoglobin in patients with methemoglobinemia. Monitor arterial blood gases; pulse oximetry may be unreliable (falsely high values) in patients with methemoglobinemia, especially following methylene or toluidine blue therapy.
    B) Urinalysis positive for blood with few or no RBC's is an early indication of hemolysis.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) Do NOT induce emesis.
    B) GASTRIC LAVAGE: Consider after ingestion of a potentially life-threatening amount of poison if it can be performed soon after ingestion (generally within 1 hour). Protect airway by placement in the head down left lateral decubitus position or by endotracheal intubation. Control any seizures first.
    1) CONTRAINDICATIONS: Loss of airway protective reflexes or decreased level of consciousness in unintubated patients; following ingestion of corrosives; hydrocarbons (high aspiration potential); patients at risk of hemorrhage or gastrointestinal perforation; and trivial or non-toxic ingestion.
    C) ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.
    D) METHEMOGLOBINEMIA: Determine the methemoglobin concentration and evaluate the patient for clinical effects of methemoglobinemia (ie, dyspnea, headache, fatigue, CNS depression, tachycardia, metabolic acidosis). Treat patients with symptomatic methemoglobinemia with methylene blue (this usually occurs at methemoglobin concentrations above 20% to 30%, but may occur at lower methemoglobin concentrations in patients with anemia, or underlying pulmonary or cardiovascular disorders). Administer oxygen while preparing for methylene blue therapy.
    E) METHYLENE BLUE: INITIAL DOSE/ADULT OR CHILD: 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is available as follows: 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules and 10 mg/1 mL (1% solution) vials. Additional doses may sometimes be required. Improvement is usually noted shortly after administration if diagnosis is correct. Consider other diagnoses or treatment options if no improvement has been observed after several doses. If intravenous access cannot be established, methylene blue may also be given by intraosseous infusion. Methylene blue should not be given by subcutaneous or intrathecal injection. NEONATES: DOSE: 0.3 to 1 mg/kg.
    F) Concomitant use of methylene blue with serotonergic drugs, including serotonin reuptake inhibitors (SRIs), selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), norepinephrine-dopamine reuptake inhibitors (NDRIs), triptans, and ergot alkaloids may increase the risk of potentially fatal serotonin syndrome.
    G) Administer 100% supplemental oxygen to patients with symptomatic methemoglobinemia. Consider hyperbaric oxygen therapy in patients refractory to methylene blue. Exchange transfusion may be necessary. Hemodialysis may be considered to remove the aniline in severe cases.
    H) HYPOTENSION: Infuse 10 to 20 mL/kg isotonic fluid. If hypotension persists, administer dopamine (5 to 20 mcg/kg/min) or norepinephrine (ADULT: begin infusion at 0.5 to 1 mcg/min; CHILD: begin infusion at 0.1 mcg/kg/min); titrate to desired response.
    0.4.3) INHALATION EXPOSURE
    A) INHALATION: Move patient to fresh air. Monitor for respiratory distress. If cough or difficulty breathing develops, evaluate for respiratory tract irritation, bronchitis, or pneumonitis. Administer oxygen and assist ventilation as required. Treat bronchospasm with an inhaled beta2-adrenergic agonist. Consider systemic corticosteroids in patients with significant bronchospasm.
    B) METHEMOGLOBINEMIA: Determine the methemoglobin concentration and evaluate the patient for clinical effects of methemoglobinemia (ie, dyspnea, headache, fatigue, CNS depression, tachycardia, metabolic acidosis). Treat patients with symptomatic methemoglobinemia with methylene blue (this usually occurs at methemoglobin concentrations above 20% to 30%, but may occur at lower methemoglobin concentrations in patients with anemia, or underlying pulmonary or cardiovascular disorders). Administer oxygen while preparing for methylene blue therapy.
    C) METHYLENE BLUE: INITIAL DOSE/ADULT OR CHILD: 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is available as follows: 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules and 10 mg/1 mL (1% solution) vials. Additional doses may sometimes be required. Improvement is usually noted shortly after administration if diagnosis is correct. Consider other diagnoses or treatment options if no improvement has been observed after several doses. If intravenous access cannot be established, methylene blue may also be given by intraosseous infusion. Methylene blue should not be given by subcutaneous or intrathecal injection. NEONATES: DOSE: 0.3 to 1 mg/kg.
    D) Concomitant use of methylene blue with serotonergic drugs, including serotonin reuptake inhibitors (SRIs), selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), norepinephrine-dopamine reuptake inhibitors (NDRIs), triptans, and ergot alkaloids may increase the risk of potentially fatal serotonin syndrome.
    E) Administer 100% supplemental oxygen to patients with symptomatic methemoglobinemia. Consider hyperbaric oxygen therapy in patients who are refractory to methylene blue therapy. Exchange transfusion may be necessary. Hemodialysis may be considered to remove the aniline in severe cases.
    0.4.4) EYE EXPOSURE
    A) DECONTAMINATION: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, the patient should be seen in a healthcare facility.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).
    2) Some chemicals can produce systemic poisoning by absorption through intact skin. Carefully observe patients with dermal exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    3) METHEMOGLOBINEMIA: Determine the methemoglobin concentration and evaluate the patient for clinical effects of methemoglobinemia (ie, dyspnea, headache, fatigue, CNS depression, tachycardia, metabolic acidosis). Treat patients with symptomatic methemoglobinemia with methylene blue (this usually occurs at methemoglobin concentrations above 20% to 30%, but may occur at lower methemoglobin concentrations in patients with anemia, or underlying pulmonary or cardiovascular disorders). Administer oxygen while preparing for methylene blue therapy.
    4) METHYLENE BLUE: INITIAL DOSE/ADULT OR CHILD: 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is available as follows: 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules and 10 mg/1 mL (1% solution) vials. Additional doses may sometimes be required. Improvement is usually noted shortly after administration if diagnosis is correct. Consider other diagnoses or treatment options if no improvement has been observed after several doses. If intravenous access cannot be established, methylene blue may also be given by intraosseous infusion. Methylene blue should not be given by subcutaneous or intrathecal injection. NEONATES: DOSE: 0.3 to 1 mg/kg.
    5) Concomitant use of methylene blue with serotonergic drugs, including serotonin reuptake inhibitors (SRIs), selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), norepinephrine-dopamine reuptake inhibitors (NDRIs), triptans, and ergot alkaloids may increase the risk of potentially fatal serotonin syndrome.
    6) Administer 100% supplemental oxygen to patients with symptomatic methemoglobinemia. Consider hyperbaric oxygen therapy in patients who are refractory to methylene blue therapy. Exchange transfusion may be necessary. Hemodialysis may be considered to remove the aniline in severe cases.
    7) Treat dermal irritation or burns with standard topical therapy. Patients developing dermal hypersensitivity reactions may require treatment with systemic or topical corticosteroids or antihistamines.

Range Of Toxicity

    A) As little as 1 gram of ingested aniline has been fatal in a human. The mean lethal ingested dose for humans has been estimated to be in the range of 15 to 30 grams.

Clinical Effects

Summary Of Exposure

    A) WITH POISONING/EXPOSURE
    1) Aniline is a skin and eye irritant and a mild dermal sensitizer. It is rapidly absorbed by all routes and induces methemoglobinemia. Symptoms of methemoglobinemia include cyanosis, headache, dizziness, weakness, lethargy, loss of coordination, dyspnea, coma, and death. A Heinz-body hemolytic crisis may follow the development of methemoglobinemia by 2 to 7 days. Heart, liver, and kidney effects may be secondary to hemolysis.
    a) Additional signs and symptoms of exposure may include photophobia, visual disturbances, sluggish pupillary reaction, tinnitus, speech disturbances, anorexia, nausea, colicky pain, muscle pain, faintness, paresthesias, tremor, seizures, cardiac dysrhythmias, and heart block. Urinary signs and symptoms may include painful micturition, hemoglobinuria, methemoglobinuria, hematuria, oliguria, and renal insufficiency.

Vital Signs

    3.3.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Acute poisoning may cause tachycardia and tachypnea.
    3.3.5) PULSE
    A) WITH POISONING/EXPOSURE
    1) Patients with acute poisoning may have a rapid, feeble pulse (Anon, 1979).

Heent

    3.4.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Cyanosis may occur. Corneal damage, discoloration, and mild to severe irritation of the eyes have been noted.
    3.4.2) HEAD
    A) WITH POISONING/EXPOSURE
    1) In acute methemoglobinemia, the lips, tongue, and mucous membranes may turn navy blue to black; skin is slate gray (Gosselin et al, 1984).
    3.4.3) EYES
    A) WITH POISONING/EXPOSURE
    1) The liquid is mildly irritating to the eyes and may cause corneal damage (Proctor & Hughes, 1978).
    2) During acute cyanosis from methemoglobinemia, the blood vessels of the conjunctiva and retina may appear discolored as if filled with ink, and the ocular fundus may be violet-colored (Grant, 1993).
    3) Liquid aniline was a severe primary irritant in rabbit eyes at 102 mg in the standard Draize test. It was a moderate irritant at 20 mg for 24 hours (RTECS , 2002).

Cardiovascular

    3.5.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Cardiovascular collapse and dysrhythmias have been noted. Subendocardial necrosis has been seen in exposed experimental animals but has not been reported in humans.
    3.5.2) CLINICAL EFFECTS
    A) TACHYCARDIA
    1) WITH POISONING/EXPOSURE
    a) Patients with acute poisoning may have a rapid, feeble pulse (Anon, 1979).
    1) ECG changes that occur with aniline poisoning are reversible as the patient recovers (Casciano, 1952; Jacobson, 1952).
    2) CASE REPORT: Sinus tachycardia was reported in a 35-year-old man following dermal exposure to a petrol octane booster containing 80% aniline (Cummings et al, 1994).
    B) HYPOTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) Death is usually from cardiovascular collapse rather than respiratory arrest (Gosselin et al, 1984).
    3.5.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) SUBENDOCARDIAL NECROSIS
    a) METABOLITE: Rats dosed by gavage with the aniline metabolite N-phenylhydroxylamine developed methemoglobinemia, splenotoxicity, and acute and resolving subendocardial necrosis mainly in the left ventricle (Khan et al, 1998). This effect has not been reported in exposed humans.

Neurologic

    3.7.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Severe headache, CNS disturbances, and tremor may occur. CNS depression may be a result of aniline-induced methemoglobinemia.
    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH POISONING/EXPOSURE
    a) Severe headache may occur as a result of the functional hypoxia (Gosselin et al, 1984).
    B) CENTRAL NERVOUS SYSTEM DEFICIT
    1) WITH POISONING/EXPOSURE
    a) Acute poisoning with aniline can produce CNS disturbances, probably secondary to hypoxia caused by methemoglobinemia, including -
    1) Headache
    2) Tinnitus
    3) Confusion
    4) Faintness
    5) Dizziness
    6) Disorientation
    7) Loss of coordination
    8) Lethargy
    9) Fatigue
    10) Drowsiness
    11) Paresthesias of the extremities
    12) Muscle pain
    13) Tremor
    14) Photophobia
    15) Speech disturbances
    16) Weakness of vision
    17) Sluggish pupillary reaction
    18) Loss of consciousness
    19) Coma
    1) (Yamazaki et al, 2001; HSDB , 1999; Grant, 1993)NIOSH, 1990; (Proctor et al, 1988; EPA, 1985; Gosselin et al, 1984a)
    b) In 1981, 80 patients in Spain developed toxic oil syndrome (TOS) after ingesting rapeseed oil contaminated with 2% aniline. A follow-up study 18 years after the exposure revealed statistically significant evidence of persistent neurological effects. The referent group (age- and sex-frequency-matched unexposed subjects) consisted of 79 patients from the same geographical area.
    1) Traditional neurologic examinations revealed no differences between the 2 groups with the exception of increased upper limb pain and decreased lower limb superficial sensation in the exposed group. Quantitative neurobehavioral and neurophysiological testing revealed a variety of changes in the TOS group compared with the referent group. Neurophysiological changes included decreased muscular strength, increased vibration threshold, and increased finger tapping test of motor quickness and coordination. Cognitive (neurobehavioral) testing demonstrated increases simple reaction time latency, sequence B latency, and auditory digit span test. Although all differences were evident in both sexes, they were more prominent in females (Posada de la Paz et al, 2003).
    C) TREMOR
    1) WITH POISONING/EXPOSURE
    a) Tremor may occur (O'Donoghue, 1985).
    D) OPISTHOTONUS
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Decorticate posturing was reported in a 4-year-old girl 13 hours following ingestion of 1 teaspoonful of aniline solution and development of a methemoglobin level of 77% (Mier, 1988).
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) PARALYSIS
    a) RATS: Single oral doses of aniline (500, 750, or 1000 mg/kg) were administered to 4-week-old male rats and single 800 mg/kg doses were administered to 7- or 10-week-old male rats. Neurotoxic changes of hindlimb paralysis and spongy changes with myelin vacuolation were reported in the higher dosage groups. No treatment-related neurobehavioral or morphologic abnormalities were found in the rats receiving 800 mg/kg of aniline (Okazaki et al, 2001).

Gastrointestinal

    3.8.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Nausea and vomiting can occur.
    3.8.2) CLINICAL EFFECTS
    A) VOMITING
    1) WITH POISONING/EXPOSURE
    a) Nausea and vomiting can occur in acute aniline poisoning (Mier, 1988; Rosenstock & Cullen, 1986; EPA, 1985).

Hepatic

    3.9.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Liver damage and jaundice may occur in patients with aniline poisoning.
    2) Aniline-treated rats had slightly decreased hepatic alkaline phosphate content and normal amino acids.
    3.9.2) CLINICAL EFFECTS
    A) LIVER DAMAGE
    1) WITH POISONING/EXPOSURE
    a) Liver damage and jaundice may occur in aniline poisoning (Lewis, 1996). In 2 subjects, doses of 45 to 65 milligrams produced a slight increase in serum bilirubin (HSDB , 1999).
    1) Liver injury is uncommon except in cases of severe hemolysis (Gosselin et al, 1984).
    2) PATHOLOGY FINDINGS: Necropsy findings include injury to the liver in acute aniline poisoning fatalities (HSDB , 1999).
    3.9.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HEPATIC ENZYMES ABNORMAL
    a) RATS treated with aniline had no change in the content of amino acids and a slight reduction of alkaline phosphate content in the liver (Pletcher et al, 1953).

Genitourinary

    3.10.1) SUMMARY
    A) Hematuria, gynecological disorders, and nephrosis have been noted.
    3.10.2) CLINICAL EFFECTS
    A) BLOOD IN URINE
    1) WITH POISONING/EXPOSURE
    a) Acute aniline poisoning can cause dysuria, hematuria, hemoglobin or hematoporphyrin in the urine, and decreased urine output (EPA, 1985). Microscopic hematuria was reported in a 4-year-old girl following ingestion of an aniline solution (Mier, 1988).
    1) Urine may be dark red or wine-colored (HSDB , 1999).
    B) ABNORMAL RENAL FUNCTION
    1) WITH POISONING/EXPOSURE
    a) PATHOLOGY FINDINGS: Necropsy findings include injury to the kidneys in acute aniline poisoning fatalities. Bladder wall ulceration and necrosis may be seen (HSDB , 1999).
    C) HEMOGLOBINURIA
    1) WITH POISONING/EXPOSURE
    a) Five patients with a history of occupational exposure to benzene and aniline developed paroxysmal nocturnal hemoglobinuria, as diagnosed by a positive acidified serum lysis (Ham's) test and flow cytometric demonstration of GPI-linked membrane protein deficiencies on the surface of red and white blood cells (Kwong & Chan, 1993).
    3.10.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) NEPHROSIS
    a) Rats treated with aniline developed slight nephrosis (Pletscher et al, 1953).

Hematologic

    3.13.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Methemoglobinemia and hemolytic anemia may occur in acute aniline poisoning. Alcohol interaction may intensify the activity in inducing methemoglobinemia.
    3.13.2) CLINICAL EFFECTS
    A) METHEMOGLOBINEMIA
    1) WITH POISONING/EXPOSURE
    a) Severe and prolonged methemoglobinemia has been reported with aniline poisoning after ingestion and after dermal exposure.
    b) The main systemic effect of acute aniline poisoning is the production of methemoglobinemia resulting in cyanosis. The blood is brown-black in color even when aerated (Gosselin et al, 1984).
    1) DERMAL ABSORPTION: Aniline is rapidly absorbed through the skin, even from exposures only to the vapors. This is often the main source of industrial poisonings (Harbison, 1998). A small amount absorbed from contaminated clothing or shoes may cause intoxication (Proctor et al, 1988). The onset of symptoms of methemoglobinemia following skin absorption may be delayed for several hours. Headache is often the first symptom and may become quite intense as the severity of methemoglobinemia progresses (Gosselin et al, 1984). Patients identified with G6PD-deficiency should be treated with methylene blue cautiously, as development of severe Heinz body hemolytic anemia may occur (Liao et al, 2001).
    2) CYANOSIS may occur when the methemoglobin concentration is 10% to 15% or greater; blueness develops first in the earlobes, nose, and lips. The otherwise healthy patient is usually asymptomatic until the methemoglobin concentration reaches approximately 30% to 40%, at which time the patient may experience weakness and dizziness (Hall et al, 1986).
    3) With up to 70% methemoglobinemia, the patient may experience ataxia, dyspnea on mild exertion, and tachycardia. Coma may ensue with methemoglobin levels greater than 70%; the lethal level is estimated to be 85% to 90% (Hall et al, 1986).
    c) ETHANOL: The activity of aniline in inducing methemoglobinemia may be intensified by alcohol (Jung, 1939).
    d) CASE REPORTS: Poisoning resulting in methemoglobinemia has been reported from aniline-containing marking ink on clothing and diapers in newborn nurseries (Smith, 1992)Ramsay & Harvey, 1959; (Munn, 1957; Pickup & Eeles, 1953). It has also been reported when approximately 35 milliliters of liquid aniline was spilled on a patient's abdomen (Casciano, 1952).
    e) Cyanosis in newborn infants at a hospital was discovered to be due to an aniline dye-containing ink on the diapers. At least 15% methemoglobinemia was detected. The infants were treated with methylene blue (Smith, 1992).
    f) CASE REPORT: A 35-year-old man developed methemoglobinemia of 17.8% after accidentally splashing a petrol octane booster containing 80% aniline on the skin (Cummings et al, 1994).
    g) CASE REPORT: A methemoglobin level of 49% was seen in a 33-year-old man who was exposed dermally to aniline when his clothing was sprayed accidentally (Phillips et al, 1990).
    h) CASE REPORT: A methemoglobin level of 68% was measured in 4-year-old girl 6 hours following ingestion of 1 teaspoonful of aniline solution. Treatment with methylene blue was started and methemoglobin levels initially decreased. Twelve hours later, methemoglobin levels began increasing and reached 77%. Decorticate posturing was present. Exchange transfusion successfully decreased methemoglobin levels to normal (Mier, 1988).
    i) CASE REPORT: Accidental dermal exposure to aniline dye resulted in acute methemoglobinemia in a worker with G6PD deficiency. Initial good response to methylene blue was reported; however, mild methemoglobinemia recurred, followed by severe Heinz body hemolytic anemia 3 days after treatment. Hydration and packed blood transfusion were performed and the patient recovered uneventfully (Liao et al, 2001).
    j) CASE REPORT: Methemoglobinemia (45% in blood approximately 8 to 9 hours postmortem) was reported in a 47-year-old man following the ingestion of an estimated 2.42 grams of propanil, an aniline insecticide. Propanil is metabolized in the liver to 3,4-dichloroaniline, which produces methemoglobinemia. Following autopsy, death was attributed to anoxemia from CNS depression and methemoglobinemia, and respiratory and circulatory failure (Yamazaki et al, 2001).
    k) CASE REPORT: Severe methemoglobinemia (72% methemoglobin fraction and coma) developed in a 39-year-old woman who ingested 125 mL of an aniline and methanol containing shoe dye. Onset of methemoglobinemia was within 90 minutes, and she required methylene blue treatment for 3 days because of recurrent methemoglobinemia. She also developed mild sulfhemoglobinemia (5.1%) and hemolysis but recovered(Katz et al, 2004).
    l) CASE REPORTS: Two male patients (33 years old and 34 years old) developed methemoglobinemia after ingesting a liquid that contained aniline instead of the intended substance, 2C-E (4-ethyl-2,5-dimethoxyphenethylamine), a psychoactive stimulant purchased via the Internet. The methemoglobin concentrations of both patients peaked at 79.6% and 74.4%, respectively, at 6 to 8 hours postingestion. Methemoglobin concentrations of both patients decreased to approximately 10% after receiving a total of 4 to 5 doses of methylene blue 1 mg/kg (Centers for Disease Control and Prevention (CDC), 2012).
    B) HEMOLYTIC ANEMIA
    1) WITH POISONING/EXPOSURE
    a) Methemoglobinemia may be followed by Heinz-body hemolytic anemia after 2 to 7 days, especially if methylene blue has been administered (Kearney et al, 1984; Harvey & Keitt, 1983; Harrison, 1977; Lubash, 1964) and especially if the patient has been identified with G6PD deficiency (Liao et al, 2001).
    b) CASE REPORT: Kearney et al (1984) report jaundice, increasing bilirubin and amino transferase levels, and a serum LDH level of 3630 International Units/liter 20 hours following ingestion of 1 to 2 ounces aniline(Kearney et al, 1984). Heinz bodies were present, and a diagnosis of Heinz-body hemolytic anemia was made.
    c) CASE REPORT: Severe methemoglobinemia developed in a 39-year-old woman who ingested 125 mL of an aniline and methanol containing shoe dye. Her hemoglobin gradually dropped over several days, with RBC fragments and spherocytes on peripheral smear, and she received 4 units of packed cells (Katz et al, 2004).
    d) CASE REPORT: A 33-year-old man developed hemolysis after receiving methylene blue treatment for methemoglobinemia secondary to unintentional ingestion of a liquid containing aniline instead of the intended substance, 2C-E (4-ethyl-2,5-dimethoxyphenethylamine), a psychoactive stimulant purchased via the Internet. Repeat measurements of the patient's methemoglobin concentration revealed that his methemoglobin concentration peaked at 79.6% at 6 hours postingestion. Following administration of a total of 5 methylene blue 1 mg/kg doses over a 2-day period, the patient's methemoglobin concentration decreased to 11%; however, on hospital day 5, his hemoglobin concentration was 5.7 g/dL, his haptoglobin concentration was less than 30 mg/dL (normal, 41 to 165 mg/dL), and his lactate dehydrogenase (LDH) concentration was 2005 units/L (normal 105 to 333 units/L), indicating the development of acute hemolysis. With administration of packed red blood cells, daily plasmapheresis for 2 days as well as 1 session on hospital day 8, and 1 complete exchange transfusion, the patient recovered with a decrease in his LDH concentration (158 units/L) and an increase and stabilization of his hemoglobin concentration (9.5 g/dL) (Centers for Disease Control and Prevention (CDC), 2012).
    C) SULFHEMOGLOBINEMIA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Severe methemoglobinemia (72%) and hemolysis developed in a 39-year-old woman who ingested 125 mL of an aniline and methanol containing shoe dye. She also developed sulfhemoglobinemia (5.1%) 7 days after her exposure. She recovered with supportive care, methylene blue, and transfusion (Katz et al, 2004).
    3.13.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) METHEMOGLOBINEMIA
    a) Aniline has also produced methemoglobinemia and hemolysis in mice, rats, rabbits, cats, and dogs (IARC, 1982).
    1) Methemoglobin levels in rats rose to maximum within 30 minutes after single oral doses of aniline. Lipid peroxidation in the spleen rose to maximum at 24 hours post-dosing, reflected in malondialdehyde-protein adduct formation and increased splenic weights.
    a) Congestion of splenic blood vessels and expanded red pulp were observed at 24 and 48 hours after dosing. Free radical-mediated reactions, it was suggested, could be the potential mechanism of aniline toxicity in the spleen (Khan et al, 1997b).
    2) N-phenylhydroxylamine (PHA), a principal metabolite of aniline, was given in graded doses to rats by gavage. Rats were sacrificed 24 hours post-dosing. Dose-related increases in methemoglobin were found, as were spleen-to-body-weight ratios. Splenic lipid peroxidation was evident in all PHA-treated rats, as was splenic congestion.
    a) Cardiac lesions were acute and resolving multifocal subendocardial necrosis, mostly in left ventricles. These findings suggest further that oxidative stress is intrinsic in splenic aniline toxicity. Direct cardiotoxicity may also be involved (Khan et al, 1998).
    3) Rodents (mice, rats, rabbits) are more resistant to the induction of methemoglobinemia than other mammalian species because they have higher levels of methemoglobin reductase than humans, dogs, or cats. Dose-response behavior in the rodent species should thus not be extrapolated to humans (Gosselin et al, 1984).
    b) In experimental animals, acute poisoning with aniline resulted in the development of methemoglobinemia, sulfhemoglobinemia, the appearance of Heinz bodies, and a disturbance in hemoglobin stability; subacute poisoning induced the formation of nitroxyhemoglobin (Avazdai, 1972).

Dermatologic

    3.14.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Dermal absorption is rapid. Cyanosis, moderate skin irritation and sensitization, and dermatitis have been noted.
    3.14.2) CLINICAL EFFECTS
    A) CYANOSIS
    1) WITH POISONING/EXPOSURE
    a) The color of the skin in acute poisonings has been described as slate-blue or slate-gray; lips and mucous membranes may be brown or navy-blue (Cummings et al, 1994; Whelan, 1984; Harrison, 1977). Cyanosis due to induction of methemoglobinemia does not improve with inhalation of 100% oxygen (Hall et al, 1986).
    B) CONTACT DERMATITIS
    1) WITH POISONING/EXPOSURE
    a) Aniline is a mild sensitizer and can cause allergic contact dermatitis (Lewis, 1996; HSDB , 1991).
    3.14.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) Aniline was a moderate skin irritant in rabbits at 20 mg for 24 hours in the standard Draize test (RTECS , 1999).

Endocrine

    3.16.1) SUMMARY
    A) Adrenal effects have been found in experimental animals.
    3.16.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) ADRENAL HYPERCORTICISM
    a) Rats given aniline for 1 to 2 weeks developed adrenal hyperplasia (Kovacs et al, 1971). Aniline lowers the plasma corticosterone level and causes adrenocortical enlargement in rats (Clayton & Clayton, 1982).

Immunologic

    3.19.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Aniline poisoning can cause allergic contact dermatitis.
    3.19.2) CLINICAL EFFECTS
    A) CONTACT DERMATITIS
    1) WITH POISONING/EXPOSURE
    a) Aniline is a mild sensitizer and can cause allergic contact dermatitis (Lewis, 1996).
    b) RELATED COMPOUNDS: Methylenedianiline was positive in skin patch tests in persons who had developed allergic dermatitis from polyurethane molding operations (Emmett, 1976).

Reproductive

    3.20.1) SUMMARY
    A) A high incidence of gynecological disorders and excess frequency of spontaneous abortions have been noted. The fetal liver can n-oxygenate aniline to form phenylhydroxylamine. Fetal effects include higher levels of methemoglobin than those found in the mother. Fetal poisoning may occur.
    B) At the time of this review, no data were available to assess the potential effects of exposure to aniline during lactation.
    C) No information about possible male reproductive effects was found in available references at the time of this review
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) LACK OF EFFECT
    a) Aniline hydrochloride was not teratogenic in rats (Wolkowski-Tyl et al, 1981).
    b) Aniline was not teratogenic in Fischer 344 rats when given by gavage as the hydrochloride at doses as high as 100 mg/kg/day (Research Triangle Institute, 2000).
    2) GROWTH RETARDED
    a) RODENTS - An effect on growth statistics was observed in the mouse or rat (Proctor et al, 1988; RTECS , 1991).
    3.20.3) EFFECTS IN PREGNANCY
    A) HUMANS
    1) ABORTION
    a) Russian women working in the aniline dye industry had a higher incidence of menstrual and ovarian function disorders than a control group (48 percent vs 3 percent). The highest frequency of spontaneous abortions was in women with low chemical exposure but in otherwise strenuous jobs (Podluzhnyi, 1979).
    2) FETAL DISTRESS
    a) There has been some speculation that methemoglobinemia may be especially harmful to the fetus:
    1) Infants, who would have had high levels of residual fetal hemoglobin, were especially sensitive to cyanosis induced by aniline in laundry marking dyes used on diapers (Rayner, 1986).
    2) Aniline poisoning has been reported from dermal exposure to marking ink on clothing and diapers in newborn nurseries (Pickup & Eeles, 1953; Munn, 1957) Ramsay & Harvey, 1959).
    3) Fetal hemoglobin is more easily oxidized to methemoglobin than the adult form, and infants have impaired ability to reduce methemoglobin back to normal hemoglobin (Ross & Desforges, 1959). These two factors result in theoretically higher levels of methemoglobin in the fetus than in the mother exposed to the same conditions.
    4) Theoretically, the fetus would be most sensitive during the last trimester when the oxygen demand is greatest. Effects of methemoglobinemia on the fetus would be expected to be similar to those known to be produced by carbon monoxide (i.e., CNS dysfunction and delayed neuromotor development in the absence of overt structural malformations). There are, however, no reported cases of prenatal effects from methemoglobinemia in humans.
    b) The fetal liver can N-oxygenate aniline to form phenylhydroxylamine, the metabolite thought to be responsible for inducing methemoglobinemia from aniline (Rane & Ackermann, 1972).
    c) CASE SERIES - In one study, slightly higher levels of methemoglobin were found in women who spontaneously aborted or threatened to abort in the first trimester (Schmitz, 1961).
    d) Aniline can cross the placental barrier and may poison the fetus (Harley & Celermajer, 1970).
    B) ANIMAL STUDIES
    1) METHEMOGLOBINEMIA
    a) In a study of experimental animals, signs of maternal toxicity included methemoglobinemia, increased relative spleen weight, decreased red blood cell count, and hematologic changes indicative of increased hematopoietic activity (Proctor et al, 1988).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of exposure to aniline during lactation.

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS62-53-3 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) IARC Classification
    a) Listed as: Aniline
    b) Carcinogen Rating: 3
    1) The agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans. This category is used most commonly for agents, mixtures and exposure circumstances for which the evidence of carcinogenicity is inadequate in humans and inadequate or limited in experimental animals. Exceptionally, agents (mixtures) for which the evidence of carcinogenicity is inadequate in humans but sufficient in experimental animals may be placed in this category when there is strong evidence that the mechanism of carcinogenicity in experimental animals does not operate in humans. Agents, mixtures and exposure circumstances that do not fall into any other group are also placed in this category.
    3.21.3) HUMAN STUDIES
    A) LACK OF INFORMATION
    1) There is inadequate evidence that aniline is a human carcinogen (IARC, 1982).
    2) Early reports of bladder cancer in persons occupationally exposed to aniline were complicated by the presence of carcinogenic impurities and other substances (Ward et al, 1991). Aniline itself is believed NOT to be a human carcinogen (IARC, 1982; Hathaway et al, 1996). It is considered to be a possible human carcinogen by the Canadian government (Gomes et al, 1994).
    3) There is little evidence of increased risk of bladder cancer in persons exposed only to pure aniline (IARC, 1982); however, other sources report that long-term exposure to aniline dye manufacture has been associated with malignant bladder tumors (Lewis, 1996; Ward et al, 1991).
    4) NIOSH has issued an alert to prevent bladder cancers from occupational aniline exposure (NIOSH, 1991). This Alert was based on a recent study by Ward et al (1991), which showed a duration-related increase in bladder cancers among rubber additives workers exposed to ortho-toluidine and aniline. A total of 13 cases of bladder cancer were found, compared with 3.6 expected (Ruder et al, 1992).
    5) Excess risk of bladder cancer was strongly associated with latency (time since first employment). Workers with less than 10 years latency had no increased risk, those with 10 to 20 years had a 2-fold excess risk, and persons with at least 20 years had an excess risk of 16.4 (Ruder et al, 1992).
    6) While aniline was thought not to be the main cause of these cancers, its possible role could not be excluded. A minor contaminant (the known human carcinogen, 4-aminobiphenyl), was also tentatively excluded as the cause of these bladder tumors, because it was present only at very low levels; the most likely carcinogen was ortho-toluidine (Ward et al, 1991).
    7) The conclusion by Ward has been criticized because 4-aminobiphenyl is a very potent human carcinogen; even the low levels present may have been sufficient to explain the findings (Tannenbaum, 1991).
    3.21.4) ANIMAL STUDIES
    A) CARCINOMA
    1) There is LIMITED EVIDENCE that aniline has been carcinogenic in experimental animals (IARC, 1982).
    2) The original positive study by Yamazaki & Sato in 1937 is now considered unreliable (IARC, 1982).
    3) Aniline hydrochloride did not induce tumors in male or female mice in a 2-year feeding study at doses of 6000 or 12,000 mg/kg (IARC, 1982).
    4) No tumors were found in the bladder, liver, spleen, or kidneys of rats given 22 mg/day of aniline in the drinking water in a lifetime study. No other tissues were examined (IARC, 1982).
    5) Rats fed aniline at 3000 or 6000 mg/kg for 103 weeks had fibrosarcomas or sarcomas in a dose-related trend in the spleen and/or abdominal cavity. Hemangiosarcomas were seen in the spleen and body cavities
    6) Aniline did not produce tumors when injected subcutaneously in mice in one 2-year study or in another study lasting for 12 or 15 months (IARC, 1982).

Genotoxicity

    A) DNA damage, DNA repair, mutations, and chromosome aberrations have been observed in experimental animals.
    B) Aniline has produced mixed results in short-term genetic assays.

Respiratory

    3.6.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Signs of hypoxia may be present.
    2) Pulmonary infiltrates, respiratory failure, and pulmonary hypertension have been attributed to exposure to rapeseed oil denatured in part with aniline as part of the "toxic oil syndrome."
    3.6.2) CLINICAL EFFECTS
    A) HYPOXEMIA
    1) WITH POISONING/EXPOSURE
    a) Although many signs of hypoxia may be present, there are generally no signs of pulmonary insufficiency. Patients with acute poisoning may experience dyspnea (Gosselin et al, 1984).
    b) After accidentally ingesting 1 to 2 ounces aniline, a 32-year-old man was admitted to the emergency department with no pulse, apneic, and cyanotic. Following resuscitation, oxygen saturation was 28% (Kearney et al, 1984).
    B) PNEUMONITIS
    1) WITH POISONING/EXPOSURE
    a) Patients with toxic oil syndrome (from exposure to rapeseed oil denatured in part with aniline) sometimes developed coughing, dyspnea, and pulmonary infiltrates in the acute phase. Death during the acute phase was usually due to respiratory failure. Pulmonary hypertension was a manifestation of the chronic phase (Borda et al, 1993).
    C) APNEA
    1) WITH POISONING/EXPOSURE
    a) Respiratory arrest may occur following exposure to aniline in conjunction with cyanosis and methemoglobinemia. Cummings et al (1994) report a case of a 35-year-old man who developed cyanosis and respiratory arrest 2 hours after admission to the emergency department following an accidental skin splash with a petrol octane booster containing 80% aniline(Cummings et al, 1994). 100% oxygen quickly reversed the respiratory arrest.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor methemoglobin levels, hemoglobin, hematocrit, and plasma free hemoglobin in patients with methemoglobinemia. Monitor arterial blood gases; pulse oximetry may be unreliable (falsely high values) in patients with methemoglobinemia, especially following methylene or toluidine blue therapy.
    B) Urinalysis positive for blood with few or no RBC's is an early indication of hemolysis.
    4.1.2) SERUM/BLOOD
    A) HEMATOLOGIC
    1) Aniline itself is seldom measured in human blood or serum. The extent of methemoglobinemia is considered a surrogate and is more closely related to the clinical state (Baselt, 1997).
    a) Methemoglobin is present to the extent of about 1 percent normally. Persons with levels below 20 percent are generally asymptomatic except for cyanosis. At 20 to 50 percent, dyspnea, tachycardia, headache and dizziness may occur. Coma or death may occur at levels above 60 to 70 percent (Harrison, 1977).
    2) If a patient is being treated conservatively or being observed, serum methemoglobin concentration should be initially monitored hourly until it is serially declining. If a patient is being treated with methylene blue hourly, serum methemoglobin concentration should be monitored until there is a serial decline in the serum methemoglobin concentration. After the patient has been stabilized, follow up serum methemoglobin concentrations should be obtained based on the patient's clinical condition.
    3) A chocolate-brown color of the blood which does not return immediately upon aeration is indicative of methemoglobinemia (Hathaway et al, 1996).
    4) Methemoglobinemia may be associated with hemolysis and (Heinz-Body) hemolytic anemia and may not be evident for several days.
    5) If hemolysis is suspected, examine the peripheral blood smear, monitor hemoglobin, hematocrit, plasma free hemoglobin, and other indices of hemolysis.
    6) Preplacement work examination should include complete blood count and hemoglobin and methemoglobin levels. Followup should include periodic blood counts and hematocrits (Sittig, 1991; Proctor & Hughes, 1978).
    4.1.3) URINE
    A) URINARY LEVELS
    1) Urinary p-aminophenol concentration of 10 mg/L may indicate potentially toxic exposure to aniline. A level of 20 mg/L indicates the need for medical intervention (Linch, 1974).
    2) The rate of urinary excretion of p-aminophenol may be used to estimate the absorbed dose over a range of 10 to 100 mg (Piotrowski, 1977).
    3) Urinary p-aminophenol concentrations are related to the level of methemoglobin in workers exposed to aniline (Pacseri, 1961).
    4) PHENACETIN - produces high levels of urinary p-aminophenol (up to 200 mg/L) and can interfere with interpretation of this indicator of aniline exposure (Piotrowski, 1977).
    5) Acute aniline poisoning can cause dysuria, hematuria, hemoglobin or hematoporphyrin in the urine, and decreased urine output (EPA, 1985).
    a) Urine may be dark red or wine-colored (HSDB , 1999).
    B) URINALYSIS
    1) A urinalysis that is positive for blood but which has few or no RBC's can be an early sign of hemolysis.
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) Preplacement and annual work physical examinations should be done, with emphasis on the blood, kidneys, liver, and cardiovascular system (Proctor & Hughes, 1978).

Radiographic Studies

    A) CHEST RADIOGRAPH
    1) Monitor chest x-ray in patients with respiratory tract signs or symptoms.

Methods

    A) MULTIPLE ANALYTICAL METHODS
    1) Aniline can be determined in air by adsorption onto silica, work up in n-propanol, and gas chromatography according to NIOSH Methods, Set K (Sittig, 1991).
    2) An apparatus and a method developed from the bleaching powder test have been described for rapid detection of concentrations as low as 5 ppm (Anon, 1968).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients symptomatic following exposure should be observed in a controlled setting until all signs and symptoms have fully resolved.

Monitoring

    A) Monitor methemoglobin levels, hemoglobin, hematocrit, and plasma free hemoglobin in patients with methemoglobinemia. Monitor arterial blood gases; pulse oximetry may be unreliable (falsely high values) in patients with methemoglobinemia, especially following methylene or toluidine blue therapy.
    B) Urinalysis positive for blood with few or no RBC's is an early indication of hemolysis.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) EMESIS -
    1) Because of the potential for gastrointestinal tract irritation and CNS depression, DO NOT induce emesis.
    B) ACTIVATED CHARCOAL -
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) EMESIS/NOT RECOMMENDED
    1) Do NOT induce emesis.
    B) GASTRIC LAVAGE
    1) INDICATIONS: Consider gastric lavage with a large-bore orogastric tube (ADULT: 36 to 40 French or 30 English gauge tube {external diameter 12 to 13.3 mm}; CHILD: 24 to 28 French {diameter 7.8 to 9.3 mm}) after a potentially life threatening ingestion if it can be performed soon after ingestion (generally within 60 minutes).
    a) Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.
    2) PRECAUTIONS:
    a) SEIZURE CONTROL: Is mandatory prior to gastric lavage.
    b) AIRWAY PROTECTION: Place patients in the head down left lateral decubitus position, with suction available. Patients with depressed mental status should be intubated with a cuffed endotracheal tube prior to lavage.
    3) LAVAGE FLUID:
    a) Use small aliquots of liquid. Lavage with 200 to 300 milliliters warm tap water (preferably 38 degrees Celsius) or saline per wash (in older children or adults) and 10 milliliters/kilogram body weight of normal saline in young children(Vale et al, 2004) and repeat until lavage return is clear.
    b) The volume of lavage return should approximate amount of fluid given to avoid fluid-electrolyte imbalance.
    c) CAUTION: Water should be avoided in young children because of the risk of electrolyte imbalance and water intoxication. Warm fluids avoid the risk of hypothermia in very young children and the elderly.
    4) COMPLICATIONS:
    a) Complications of gastric lavage have included: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach, fluid and electrolyte imbalance (Vale, 1997). Combative patients may be at greater risk for complications (Caravati et al, 2001).
    b) Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all poisoned patients (Vale, 1997).
    5) CONTRAINDICATIONS:
    a) Loss of airway protective reflexes or decreased level of consciousness if patient is not intubated, following ingestion of corrosive substances, hydrocarbons (high aspiration potential), patients at risk of hemorrhage or gastrointestinal perforation, or trivial or non-toxic ingestion.
    C) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) Monitor oxygenation, methemoglobin levels, hemoglobin, hematocrit, plasma free hemoglobin, urinalysis, and perhaps other indices of hemolysis. Pulse oximetry may give an erroneously high reading in a patient with methemoglobinemia.
    2) If a patient is being treated conservatively or being observed, serum methemoglobin concentration should be initially monitored hourly until it is serially declining. If a patient is being treated with methylene blue hourly, serum methemoglobin concentration should be monitored until there is a serial decline in the serum methemoglobin concentration. After the patient has been stabilized, follow-up serum methemoglobin concentrations should be obtained based on the patient's clinical condition.
    B) METHEMOGLOBINEMIA
    1) SUMMARY
    a) Determine the methemoglobin concentration and evaluate the patient for clinical effects of methemoglobinemia (ie, dyspnea, headache, fatigue, CNS depression, tachycardia, metabolic acidosis). Treat patients with symptomatic methemoglobinemia with methylene blue (this usually occurs at methemoglobin concentrations above 20% to 30%, but may occur at lower methemoglobin concentrations in patients with anemia, or underlying pulmonary or cardiovascular disorders). Administer oxygen while preparing for methylene blue therapy.
    2) METHYLENE BLUE
    a) INITIAL DOSE/ADULT OR CHILD: 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is available as follows: 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules (Prod Info PROVAYBLUE(TM) intravenous injection, 2016) and 10 mg/1 mL (1% solution) vials (Prod Info methylene blue 1% intravenous injection, 2011). REPEAT DOSES: Additional doses may be required, especially for substances with prolonged absorption, slow elimination, or those that form metabolites that produce methemoglobin. NOTE: Large doses of methylene blue may cause methemoglobinemia or hemolysis (Howland, 2006). Improvement is usually noted shortly after administration if diagnosis is correct. Consider other diagnoses or treatment options if no improvement has been observed after several doses. If intravenous access cannot be established, methylene blue may also be given by intraosseous infusion. Methylene blue should not be given by subcutaneous or intrathecal injection (Prod Info methylene blue 1% intravenous injection, 2011; Herman et al, 1999). NEONATES: DOSE: 0.3 to 1 mg/kg (Hjelt et al, 1995).
    b) CONTRAINDICATIONS: G-6-PD deficiency (methylene blue may cause hemolysis), known hypersensitivity to methylene blue, methemoglobin reductase deficiency (Shepherd & Keyes, 2004)
    c) FAILURE: Failure of methylene blue therapy suggests: inadequate dose of methylene blue, inadequate decontamination, NADPH dependent methemoglobin reductase deficiency, hemoglobin M disease, sulfhemoglobinemia, or G-6-PD deficiency. Methylene blue is reduced by methemoglobin reductase and nicotinamide adenosine dinucleotide phosphate (NADPH) to leukomethylene blue. This in turn reduces methemoglobin. Red blood cells of patients with G-6-PD deficiency do not produce enough NADPH to convert methylene blue to leukomethylene blue (do Nascimento et al, 2008).
    d) DRUG INTERACTION: Concomitant use of methylene blue with serotonergic drugs, including serotonin reuptake inhibitors (SRIs), selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), norepinephrine-dopamine reuptake inhibitors (NDRIs), triptans, and ergot alkaloids may increase the risk of potentially fatal serotonin syndrome (U.S. Food and Drug Administration, 2011; Stanford et al, 2010; Prod Info methylene blue 1% IV injection, 2011).
    3) TOLUIDINE BLUE OR TOLONIUM CHLORIDE (GERMANY)
    a) DOSE: 2 to 4 mg/kg intravenously over 5 minutes. Dose may be repeated in 30 minutes (Nemec, 2011; Lindenmann et al, 2006; Kiese et al, 1972).
    b) SIDE EFFECTS: Hypotension with rapid intravenous administration. Vomiting, diarrhea, excessive sweating, hypotension, dysrhythmias, hemolysis, agranulocytosis and acute renal insufficiency after overdose (Dunipace et al, 1992; Hix & Wilson, 1987; Winek et al, 1969; Teunis et al, 1970; Marquez & Todd, 1959).
    c) CONTRAINDICATIONS: G-6-PD deficiency; may cause hemolysis.
    4) Exchange transfusion may be required in severe cases or those refractory to methylene blue therapy (Mier, 1988). Methylene blue may be ineffective due to competition with an aniline metabolite, phenylhydroxylamine (PHA) (Mier, 1988). Methylene blue should not be given, or given with caution, to patients identified with G6PD deficiency since methylene blue may precipitate hemolytic anemia. If a history of G6PD deficiency is obscure, it is recommended to titrate the dose of methylene blue, starting with 0.3 to 0.5 mg/kg initially (Liao et al, 2001).
    5) Hyperbaric oxygen therapy can be used to ensure adequate oxygenation in patients with severe methemoglobinemia while preparations are being made for emergency exchange transfusion.
    C) OXYGEN
    1) Patients with methemoglobinemia should be administered supplemental oxygen.
    D) HEMOLYSIS
    1) Transfusion of blood or packed red blood cells may be required.
    2) Maintain a liberal urine output (2 to 4 mL/kg/hr) to help prevent renal damage from RBC breakdown products.
    E) SUPPORT
    1) Frequent vital signs monitoring and supportive care are required.
    F) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    G) AIRWAY MANAGEMENT
    1) If CNS and respiratory depression occur, ensure airway patency and adequacy of oxygenation and ventilation. Endotracheal intubation, supplemental oxygenation, and assisted ventilation could be required.

Inhalation Exposure

    6.7.1) DECONTAMINATION
    A) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
    B) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    C) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.
    6.7.2) TREATMENT
    A) PULMONARY ABSORPTION
    1) Inhalation of vapors can cause systemic poisoning resulting in methemoglobinemia and hemolysis.
    B) MONITORING OF PATIENT
    1) Monitor oxygenation, methemoglobin levels, hemoglobin, hematocrit, plasma free hemoglobin, urinalysis, and perhaps other indices of hemolysis.
    C) METHEMOGLOBINEMIA
    1) SUMMARY
    a) Determine the methemoglobin concentration and evaluate the patient for clinical effects of methemoglobinemia (ie, dyspnea, headache, fatigue, CNS depression, tachycardia, metabolic acidosis). Treat patients with symptomatic methemoglobinemia with methylene blue (this usually occurs at methemoglobin concentrations above 20% to 30%, but may occur at lower methemoglobin concentrations in patients with anemia, or underlying pulmonary or cardiovascular disorders). Administer oxygen while preparing for methylene blue therapy.
    2) METHYLENE BLUE
    a) INITIAL DOSE/ADULT OR CHILD: 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is available as follows: 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules (Prod Info PROVAYBLUE(TM) intravenous injection, 2016) and 10 mg/1 mL (1% solution) vials (Prod Info methylene blue 1% intravenous injection, 2011). REPEAT DOSES: Additional doses may be required, especially for substances with prolonged absorption, slow elimination, or those that form metabolites that produce methemoglobin. NOTE: Large doses of methylene blue may cause methemoglobinemia or hemolysis (Howland, 2006). Improvement is usually noted shortly after administration if diagnosis is correct. Consider other diagnoses or treatment options if no improvement has been observed after several doses. If intravenous access cannot be established, methylene blue may also be given by intraosseous infusion. Methylene blue should not be given by subcutaneous or intrathecal injection (Prod Info methylene blue 1% intravenous injection, 2011; Herman et al, 1999). NEONATES: DOSE: 0.3 to 1 mg/kg (Hjelt et al, 1995).
    b) CONTRAINDICATIONS: G-6-PD deficiency (methylene blue may cause hemolysis), known hypersensitivity to methylene blue, methemoglobin reductase deficiency (Shepherd & Keyes, 2004)
    c) FAILURE: Failure of methylene blue therapy suggests: inadequate dose of methylene blue, inadequate decontamination, NADPH dependent methemoglobin reductase deficiency, hemoglobin M disease, sulfhemoglobinemia, or G-6-PD deficiency. Methylene blue is reduced by methemoglobin reductase and nicotinamide adenosine dinucleotide phosphate (NADPH) to leukomethylene blue. This in turn reduces methemoglobin. Red blood cells of patients with G-6-PD deficiency do not produce enough NADPH to convert methylene blue to leukomethylene blue (do Nascimento et al, 2008).
    d) DRUG INTERACTION: Concomitant use of methylene blue with serotonergic drugs, including serotonin reuptake inhibitors (SRIs), selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), norepinephrine-dopamine reuptake inhibitors (NDRIs), triptans, and ergot alkaloids may increase the risk of potentially fatal serotonin syndrome (U.S. Food and Drug Administration, 2011; Stanford et al, 2010; Prod Info methylene blue 1% IV injection, 2011).
    3) TOLUIDINE BLUE OR TOLONIUM CHLORIDE (GERMANY)
    a) DOSE: 2 to 4 mg/kg intravenously over 5 minutes. Dose may be repeated in 30 minutes (Nemec, 2011; Lindenmann et al, 2006; Kiese et al, 1972).
    b) SIDE EFFECTS: Hypotension with rapid intravenous administration. Vomiting, diarrhea, excessive sweating, hypotension, dysrhythmias, hemolysis, agranulocytosis and acute renal insufficiency after overdose (Dunipace et al, 1992; Hix & Wilson, 1987; Winek et al, 1969; Teunis et al, 1970; Marquez & Todd, 1959).
    c) CONTRAINDICATIONS: G-6-PD deficiency; may cause hemolysis.
    4) Exchange transfusion may be required in severe cases or those refractory to methylene blue therapy (Mier, 1988). Methylene blue may be ineffective due to competition with an aniline metabolite, phenylhydroxylamine (PHA) (Mier, 1988).
    5) Hyperbaric oxygen therapy may be used to ensure adequate oxygenation in patients with severe methemoglobinemia while preparations are being made of emergency exchange transfusion.
    D) OXYGEN
    1) Patients with methemoglobinemia should be given supplemental oxygen.
    E) HEMOLYSIS
    1) Transfusion of blood or packed red blood cells may be required.
    2) Maintain liberal urine output (2 to 4 mL/kg/hr) to help prevent renal damage from RBC breakdown products.
    F) SUPPORT
    1) Frequent vital signs monitoring and supportive care are required.
    G) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    H) AIRWAY MANAGEMENT
    1) If CNS and respiratory depression occur, ensure airway patency and adequacy of oxygenation and ventilation. Endotracheal intubation, supplemental oxygenation, and assisted ventilation could be required.
    I) ENHANCED ELIMINATION PROCEDURE
    1) HEMODIALYSIS -
    a) In one reported case, the elimination of aniline was enhanced by hemodialysis (Lubash, 1964). In serious cases refractory to other treatments, hemodialysis should be considered in an attempt to remove the methemoglobin-inducing agent.
    b) If renal failure occurs secondary to hemolysis, treatment with hemodialysis may be required.
    2) EXCHANGE TRANSFUSION -
    a) Ingestion of a teaspoonful of pure aniline resulted in a methemoglobin level of 77% in a 4-year-old child. Methylene blue therapy was unsuccessful, but a 1.4 volume exchange transfusion decreased the methemoglobin level to 14 percent at the end of the procedure (Mier, 1988).
    J) PATIENT DISPOSITION
    1) OBSERVATION CRITERIA
    a) Patients symptomatic following exposure should be observed in a controlled setting until all signs and symptoms have fully resolved.
    K) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Eye Exposure

    6.8.1) DECONTAMINATION
    A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).
    6.9.2) TREATMENT
    A) IRRITATION SYMPTOM
    1) Treat dermal irritation or burns with standard topical therapy. Patients developing dermal hypersensitivity reactions may require treatment with systemic or topical corticosteroids or antihistamines.
    B) SKIN ABSORPTION
    1) Some chemicals can produce systemic poisoning by absorption through intact skin. Carefully observe patients with dermal exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    2) Dermal exposure to the vapors alone may allow systemic absorption and toxicity from methemoglobinemia and hemolysis.
    C) MONITORING OF PATIENT
    1) Monitor oxygenation, methemoglobin levels, hemoglobin, hematocrit, plasma free hemoglobin, urinalysis, and perhaps other indices of hemolysis.
    D) METHEMOGLOBINEMIA
    1) SUMMARY
    a) Determine the methemoglobin concentration and evaluate the patient for clinical effects of methemoglobinemia (ie, dyspnea, headache, fatigue, CNS depression, tachycardia, metabolic acidosis). Treat patients with symptomatic methemoglobinemia with methylene blue (this usually occurs at methemoglobin concentrations above 20% to 30%, but may occur at lower methemoglobin concentrations in patients with anemia, or underlying pulmonary or cardiovascular disorders). Administer oxygen while preparing for methylene blue therapy.
    2) METHYLENE BLUE
    a) INITIAL DOSE/ADULT OR CHILD: 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is available as follows: 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules (Prod Info PROVAYBLUE(TM) intravenous injection, 2016) and 10 mg/1 mL (1% solution) vials (Prod Info methylene blue 1% intravenous injection, 2011). REPEAT DOSES: Additional doses may be required, especially for substances with prolonged absorption, slow elimination, or those that form metabolites that produce methemoglobin. NOTE: Large doses of methylene blue may cause methemoglobinemia or hemolysis (Howland, 2006). Improvement is usually noted shortly after administration if diagnosis is correct. Consider other diagnoses or treatment options if no improvement has been observed after several doses. If intravenous access cannot be established, methylene blue may also be given by intraosseous infusion. Methylene blue should not be given by subcutaneous or intrathecal injection (Prod Info methylene blue 1% intravenous injection, 2011; Herman et al, 1999). NEONATES: DOSE: 0.3 to 1 mg/kg (Hjelt et al, 1995).
    b) CONTRAINDICATIONS: G-6-PD deficiency (methylene blue may cause hemolysis), known hypersensitivity to methylene blue, methemoglobin reductase deficiency (Shepherd & Keyes, 2004)
    c) FAILURE: Failure of methylene blue therapy suggests: inadequate dose of methylene blue, inadequate decontamination, NADPH dependent methemoglobin reductase deficiency, hemoglobin M disease, sulfhemoglobinemia, or G-6-PD deficiency. Methylene blue is reduced by methemoglobin reductase and nicotinamide adenosine dinucleotide phosphate (NADPH) to leukomethylene blue. This in turn reduces methemoglobin. Red blood cells of patients with G-6-PD deficiency do not produce enough NADPH to convert methylene blue to leukomethylene blue (do Nascimento et al, 2008).
    d) DRUG INTERACTION: Concomitant use of methylene blue with serotonergic drugs, including serotonin reuptake inhibitors (SRIs), selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), norepinephrine-dopamine reuptake inhibitors (NDRIs), triptans, and ergot alkaloids may increase the risk of potentially fatal serotonin syndrome (U.S. Food and Drug Administration, 2011; Stanford et al, 2010; Prod Info methylene blue 1% IV injection, 2011).
    3) TOLUIDINE BLUE OR TOLONIUM CHLORIDE (GERMANY)
    a) DOSE: 2 to 4 mg/kg intravenously over 5 minutes. Dose may be repeated in 30 minutes (Nemec, 2011; Lindenmann et al, 2006; Kiese et al, 1972).
    b) SIDE EFFECTS: Hypotension with rapid intravenous administration. Vomiting, diarrhea, excessive sweating, hypotension, dysrhythmias, hemolysis, agranulocytosis and acute renal insufficiency after overdose (Dunipace et al, 1992; Hix & Wilson, 1987; Winek et al, 1969; Teunis et al, 1970; Marquez & Todd, 1959).
    c) CONTRAINDICATIONS: G-6-PD deficiency; may cause hemolysis.
    4) Exchange transfusion may be required in severe cases or those refractory to methylene blue therapy (Mier, 1988). Methylene blue may be ineffective due to competition with an aniline metabolite, phenylhydroxylamine (PHA) (Mier, 1988).
    5) Hyperbaric oxygen therapy may be used to ensure adequate oxygenation in patients with severe methemoglobinemia while preparations are being made for emergency exchange transfusion.
    E) OXYGEN
    1) Patients with methemoglobinemia should be given supplemental oxygen.
    F) HEMOLYSIS
    1) Transfusion of blood or packed red blood cells may be required.
    2) Maintain liberal urine output (2 to 4 mL/kg/hr) to help prevent renal damage from RBC breakdown products.
    G) SUPPORT
    1) Frequent vital signs monitoring and supportive care are required.
    H) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    I) AIRWAY MANAGEMENT
    1) If CNS and respiratory depression occur, ensure airway patency and adequacy of oxygenation and ventilation. Endotracheal intubation, supplemental oxygenation, and assisted ventilation could be required.
    J) ENHANCED ELIMINATION PROCEDURE
    1) HEMODIALYSIS -
    a) In one reported case, the elimination of aniline was enhanced by hemodialysis (Lubash, 1964). In serious cases refractory to other treatments, hemodialysis should be considered in an attempt to remove the methemoglobin-inducing agent.
    b) If renal failure occurs secondary to hemolysis, treatment with hemodialysis may be required.
    2) EXCHANGE TRANSFUSION -
    a) Ingestion of a teaspoonful of pure aniline resulted in a methemoglobin level of 77% in a 4-year-old child. Methylene blue therapy was unsuccessful, but a 1.4 volume exchange transfusion decreased the methemoglobin level to 14 percent at the end of the procedure (Mier, 1988).
    K) PATIENT DISPOSITION
    1) OBSERVATION CRITERIA
    a) Patients symptomatic following exposure should be observed in a controlled setting until all signs and symptoms have fully resolved.
    L) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Enhanced Elimination

    A) HEMODIALYSIS
    1) In one reported case, the elimination of aniline was hastened by hemodialysis (Lubash, 1964). In serious cases refractory to other treatments, hemodialysis could be considered in an attempt to remove the methemoglobin-inducing agent.
    2) If renal failure occurs secondary to hemolysis, treatment with hemodialysis may be required.
    B) EXCHANGE TRANSFUSION
    1) Ingestion of a teaspoonful of pure aniline resulted in a methemoglobin level of 77% in a 4-year-old child. Methylene blue therapy was unsuccessful, but a 1.4 volume exchange transfusion decreased the methemoglobin level to 14 percent at the end of the procedure (Mier, 1988).

Abstracts

Case Reports

    A) OTHER
    1) Aniline was one of the toxic components in denatured and heat-processed cooking oil that caused over 20,000 cases of poisoning and about 400 deaths in Spain (Vazquez Roncero A, 1983). This group of patients has been extensively studied both for characterization of the clinical syndrome and for identification of the possible causative agent. The complex clinical picture has been named "toxic oil syndrome" (Gilsanz, 1984; Martin Escribano et al, 1984).
    a) The clinical symptoms first appeared in May 1981 and involved toxic-allergic pneumonopathy with respiratory distress, interstitial exudation, fever, itching, enlarged lymph nodes, dry cough, lower respiratory tract symptoms (dyspnea, tachypnea, nasal flaring, inspiratory retractions, rales), chest pain, headache, nausea, diarrhea, muscular and abdominal pain, rash, hepatosplenomegaly, eosinophilia, and delayed thrombotic and neurological disorders. None of the patients had methemoglobinemia. Thus this syndrome is distinct from aniline poisoning (Kilbourne et al, 1988)Casado de Frias et al, 1983; (Ross, 1981; Tabuenca, 1981).
    b) The second phase of the illness some 9 to 12 months later included neuropathy and neurogenic atrophy and myositis in some cases. Intense myalgias, violent and repeated cramps of the extremities, and paresthesias were common in children. Muscle atrophy and joint contractures were common. Death occurred in this phase usually from aspiration pneumonia secondary to respiratory muscle insufficiency (Gilsanz, 1984) Casado de Frias et al, 1983.
    c) In 35% of the pediatric patients in phase 2 of the syndrome, there were also dermatologic findings of hard and sclerotic skin with gray-brown hyperpigmented maculae. Significant weight loss occurred in the patients with the most severe skin and neuromuscular impairments. Psychiatric symptoms occurred in some of the patients (Casado de Frias et al, 1983).
    d) Over a 2-year period, altered serum glycosidase activities and most clinical abnormalities returned to normal (Cabezas-Delamare & Cabezas, 1985) Casado de Frias et al, 1983.
    e) There has been much uncertainty in identifying the causative agent, partly because samples of oil have been lost or mislabeled. The incriminated samples were olive oil adulterated with rapeseed oil that had been denatured with aniline and subsequently heat processed. It contained 500 to 2000 ppm of fatty acid anilides, mainly oleoanilide, which may have been formed from a reaction between the fatty acids and acetanilide. Free aniline was present only to the extent of 4% in samples of the oil; 69% was as fatty acid anilides, and 27% as other unknown aniline derivatives (Kilbourne et al, 1988) Vazquez Roncero et al, 1983.
    f) The unknown aniline derivatives have been identified as a fatty acid diester of 1,2-propanediol-3-aminophenyl (Vazquez Roncero A, 1983).
    g) Over 20 products of aniline and triglycerides (ester and ester amides of 3-(N-phenylamino)-1,2-propanediol) have been identified in the involved oils (Schurz et al, 1996).
    B) ADULT
    1) A 19-year-old male chemistry student accidentally pipetted a brown liquid into his mouth. Analysis of stomach contents revealed nitrobenzene and aniline. He was admitted to the hospital unconscious with lips, tongue, and mucous membranes that were navy blue. The skin was a slate-grey color. Blood was a chocolate-brown color and contained high levels of methemoglobin.
    a) Treatment including methylene blue and exchange transfusion reduced the methemoglobin level to 25%. Seven days after admission there was a hemolytic crisis (hemoglobin 4.5 g/dL). After further transfusion the patient recovered uneventfully (Harrison, 1977).
    2) A 22-year-old mechanic accidentally ingested a small amount of pure aniline oil intended for use as an octane booster. He became drowsy and cyanotic within an hour, and was given 150 mg of methylene blue upon admission to the hospital. A second methylene blue dose of 150 mg was given 9 hours later.
    a) Cyanosis gradually diminished and the patient was discharged 64 hours after exposure, only to be readmitted at 72 hours with bloody urine, jaundice, and Heinz-body hemolytic anemia. Transfusion was given on day 6. Recovery was uneventful and the patient was discharged on day 10 (Harvey & Keitt, 1983).
    3) A 21-year-old woman drank about 80 mL of aniline and was found in a coma with shock and deep cyanosis. Treatment included methylene blue and exchange transfusion. A generalized seizure and CNS depression developed. The patient had slate blue skin and mucous membranes and retinae with dark-blue retinal blood vessels. Blood was chocolate-colored and urine was dark brown (Lubash, 1964).
    a) Hemodialysis was performed for 7 hours and additional doses of methylene blue were given. Blood pressure decreased and oliguria ensued. The patient gradually regained consciousness. Skin color dramatically improved about 28 hours after exposure, but massive hemolysis followed. Seven units of packed red blood cells were given over the next 3 days. Hemolysis gradually subsided and all hematologic and renal findings were normal within a week (Lubash, 1964).
    b) Hemodialysis removed more aniline in 7 hours and 20 minutes than the kidneys did in 4 days (Lubash, 1964).
    4) A 32-year-old man ingested 1 to 2 ounces of Moraso gasoline booster and was treated with methylene blue and ascorbic acid. By 18 hours after exposure cyanosis was present and the methemoglobin level was 45%. On the third day, the patient developed jaundice, Heinz bodies, and decreased hemoglobin and hematocrit. He received 9 units of packed red cells over 5 days and was discharged with stable hematologic values (Kearney et al, 1984).
    5) A 28-year-old woman developed cyanosis from dermal absorption of Moraso high-octane booster spilled on automobile upholstery. After 2 doses of methylene blue, the patient was discharged in 24 hours. No mention was made of whether a subsequent hemolytic episode occurred (Whelan, 1984).
    C) PEDIATRIC
    1) A case of methemoglobinemia occurred when a schoolboy sat on a seat upon which aniline had been spilled; oral exposure was also suspected from his contaminated hands. He collapsed after 3 hours of exposure. Deep cyanosis was treated with intravenous methylene blue and he recovered quickly (Stening, 1951).
    a) INFANT
    1) Cyanosis was successfully treated in a 32-day-old infant who had been treated for furunculosis of the auditory meatus with only 1 drop of 10% cocaine in aniline (Tada et al, 1987).

Range Of Toxicity

Summary

    A) As little as 1 gram of ingested aniline has been fatal in a human. The mean lethal ingested dose for humans has been estimated to be in the range of 15 to 30 grams.

Minimum Lethal Exposure

    A) As little as 1 g of ingested aniline has been fatal in a human (Hathaway et al, 1996).
    B) The mean lethal dose by ingestion has been estimated at between 15 to 30 grams (Hathaway et al, 1996).

Maximum Tolerated Exposure

    A) A single oral dose of 15 mg of aniline given to volunteers had no effect (Baselt, 1997; Baselt, 2000).
    B) The minimal toxic dose of aniline has not been defined in humans, but as little as 25 milligrams produced significant elevation of methemoglobin levels in human volunteers (Hathaway et al, 1996; Jenkins et al, 1972).
    C) Inhalation exposure to vapor at 7 to 53 parts per million caused slight symptoms after several hours; a 1-hour inhalation exposure to airborne concentrations greater than 100 to 160 parts per million caused serious disturbances (ACGIH, 1991).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) GENERAL
    a) Aniline was present in the blood at 25 milligrams/liter in a woman who ingested about 80 milliliters of aniline. Methemoglobin level was 50 percent (Lubash, 1964).
    b) Aniline itself has usually not been measured in human blood or serum. The extent of methemoglobinemia is considered a surrogate and is more closely related to the clinical state (Baselt, 1997).
    1) Methemoglobin is present to the extent of about 1 percent normally.
    2) Persons with levels less than 20 percent are generally asymptomatic except for cyanosis which does not improve with inhalation of 100 percent oxygen.
    3) At levels of 20 to 50 percent, dyspnea, tachycardia, headache, and dizziness may occur.
    4) Coma or death may be seen at levels above 60 to 70 percent (Harrison, 1977).
    c) Urinary p-aminophenol concentration of 10 milligrams/Liter may indicate potentially toxic exposure to aniline; 20 milligrams/Liter indicates the need for medical intervention (Linch, 1974).
    1) The rate of urinary excretion of p-aminophenol may be used to estimate the absorbed dose over a range of 10 to 100 milligrams (Piotrowski, 1977).
    2) Urinary p-aminophenol concentrations are also related to the level of methemoglobin in workers exposed to aniline (Pacseri, 1961).

Workplace Standards

    A) ACGIH TLV Values for CAS62-53-3 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Editor's Note: The listed values are recommendations or guidelines developed by ACGIH(R) to assist in the control of health hazards. They should only be used, interpreted and applied by individuals trained in industrial hygiene. Before applying these values, it is imperative to read the introduction to each section in the current TLVs(R) and BEI(R) Book and become familiar with the constraints and limitations to their use. Always consult the Documentation of the TLVs(R) and BEIs(R) before applying these recommendations and guidelines.
    a) Adopted Value
    1) Aniline
    a) TLV:
    1) TLV-TWA: 2 ppm
    2) TLV-STEL:
    3) TLV-Ceiling:
    b) Notations and Endnotes:
    1) Carcinogenicity Category: A3
    2) Codes: BEI, Skin
    3) Definitions:
    a) A3: Confirmed Animal Carcinogen with Unknown Relevance to Humans: The agent is carcinogenic in experimental animals at a relatively high dose, by route(s) of administration, at site(s), of histologic type(s), or by mechanism(s) that may not be relevant to worker exposure. Available epidemiologic studies do not confirm an increased risk of cancer in exposed humans. Available evidence does not suggest that the agent is likely to cause cancer in humans except under uncommon or unlikely routes or levels of exposure.
    b) BEI: The BEI notation is listed when a BEI is also recommended for the substance listed. Biological monitoring should be instituted for such substances to evaluate the total exposure from all sources, including dermal, ingestion, or non-occupational.
    c) Skin: This refers to the potential significant contribution to the overall exposure by the cutaneous route, including mucous membranes and the eyes, either by contact with vapors or, of likely greater significance, by direct skin contact with the substance. It should be noted that although some materials are capable of causing irritation, dermatitis, and sensitization in workers, these properties are not considered relevant when assigning a skin notation. Rather, data from acute dermal studies and repeated dose dermal studies in animals or humans, along with the ability of the chemical to be absorbed, are integrated in the decision-making toward assignment of the skin designation. Use of the skin designation provides an alert that air sampling would not be sufficient by itself in quantifying exposure from the substance and that measures to prevent significant cutaneous absorption may be warranted. Please see "Definitions and Notations" (in TLV booklet) for full definition.
    c) TLV Basis - Critical Effect(s): MeHb-emia
    d) Molecular Weight: 93.12
    1) For gases and vapors, to convert the TLV from ppm to mg/m(3):
    a) [(TLV in ppm)(gram molecular weight of substance)]/24.45
    2) For gases and vapors, to convert the TLV from mg/m(3) to ppm:
    a) [(TLV in mg/m(3))(24.45)]/gram molecular weight of substance
    e) Additional information:

    B) NIOSH REL and IDLH Values for CAS62-53-3 (National Institute for Occupational Safety and Health, 2007):
    1) Listed as: Aniline (and homologs)
    2) REL:
    a) TWA:
    b) STEL:
    c) Ceiling:
    d) Carcinogen Listing: (Ca) NIOSH considers this substance to be a potential occupational carcinogen (See Appendix A in the NIOSH Pocket Guide to Chemical Hazards).
    e) Skin Designation: Not Listed
    f) Note(s): See Appendix A
    3) IDLH:
    a) IDLH: 100 ppm
    b) Note(s): Ca
    1) Ca: NIOSH considers this substance to be a potential occupational carcinogen (See Appendix A).

    C) Carcinogenicity Ratings for CAS62-53-3 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): A3 ; Listed as: Aniline
    a) A3 :Confirmed Animal Carcinogen with Unknown Relevance to Humans: The agent is carcinogenic in experimental animals at a relatively high dose, by route(s) of administration, at site(s), of histologic type(s), or by mechanism(s) that may not be relevant to worker exposure. Available epidemiologic studies do not confirm an increased risk of cancer in exposed humans. Available evidence does not suggest that the agent is likely to cause cancer in humans except under uncommon or unlikely routes or levels of exposure.
    2) EPA (U.S. Environmental Protection Agency, 2011): B2 ; Listed as: Aniline
    a) B2 : Probable human carcinogen - based on sufficient evidence of carcinogenicity in animals.
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): 3 ; Listed as: Aniline
    a) 3 : The agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans. This category is used most commonly for agents, mixtures and exposure circumstances for which the evidence of carcinogenicity is inadequate in humans and inadequate or limited in experimental animals. Exceptionally, agents (mixtures) for which the evidence of carcinogenicity is inadequate in humans but sufficient in experimental animals may be placed in this category when there is strong evidence that the mechanism of carcinogenicity in experimental animals does not operate in humans. Agents, mixtures and exposure circumstances that do not fall into any other group are also placed in this category.
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Ca ; Listed as: Aniline (and homologs)
    a) Ca : NIOSH considers this substance to be a potential occupational carcinogen (See Appendix A in the NIOSH Pocket Guide to Chemical Hazards).
    5) MAK (DFG, 2002): Category 3B ; Listed as: Aniline
    a) Category 3B : Substances for which in vitro or animal studies have yielded evidence of carcinogenic effects that is not sufficient for classification of the substance in one of the other categories. Further studies are required before a final decision can be made. A MAK value can be established provided no genotoxic effects have been detected. (Footnote: In the past, when a substance was classified as Category 3 it was given a MAK value provided that it had no detectable genotoxic effects. When all such substances have been examined for whether or not they may be classified in Category 4, this sentence may be omitted.)
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS62-53-3 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Listed as: Aniline and homologs
    2) Table Z-1 for Aniline and homologs:
    a) 8-hour TWA:
    1) ppm: 5
    a) Parts of vapor or gas per million parts of contaminated air by volume at 25 degrees C and 760 torr.
    2) mg/m3: 19
    a) Milligrams of substances per cubic meter of air. When entry is in this column only, the value is exact; when listed with a ppm entry, it is approximate.
    3) Ceiling Value:
    4) Skin Designation: Yes
    5) Notation(s): Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) References: ACGIH, 1991 ITI, 1995 Lewis, 2000 RTECS, 2002
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 492 mg/kg
    2) LD50- (ORAL)MOUSE:
    a) 464 mg/kg
    3) LD50- (SUBCUTANEOUS)MOUSE:
    a) 200 mg/kg
    4) LD50- (INTRAPERITONEAL)RAT:
    a) 420 mg/kg
    5) LD50- (ORAL)RAT:
    a) 250 mg/kg
    b) 440 mg/kg (ACGIH, 1991)
    6) LD50- (SKIN)RAT:
    a) 1400 mg/kg
    7) TCLo- (INHALATION)RAT:
    a) 3 mg/m(3) for 22W-intermittent -- blood and serum composition changes
    b) 5 mg/m(3) for 24H/21D-continuous -- blood effects
    c) 300 mcg/m(3) for 24H/80D continuous -- muscles changes
    d) 87 ppm for 6H/2W-intermittent -- changes in liver and spleen weight, and changes in RBC count

Pharmacology Toxicology

Toxicologic Mechanism

    A) Aniline does not react with hemoglobin to form methemoglobin in vitro; therefore metabolic activation is required for its major toxic effect (Gosselin et al, 1984).
    B) Methemoglobin is formed by the oxidation of iron in hemoglobin from the ferrous(+2) to the ferric(+3) state, in which it can no longer reversibly transport oxygen, producing symptoms of hypoxia (Harrison, 1977; Hall et al, 1986).
    C) The mechanism by which aniline induces Heinz bodies is unknown. It may possibly generate hydrogen peroxide and superoxide radicals in the presence of oxygen (Harvey & Keitt, 1983).
    1) Anilides such as those implicated in the outbreak of toxic oil syndrome in Spain may generate free radicals in the body. This has been speculated to be involved in the mechanism of their toxicity (Martin Escribano et al, 1984).
    D) In rats, aniline is splenotoxic and induces protein oxidation and lipid peroxidation in this organ (Khan et al, 1997b).
    E) In rats, a single inhalation exposure to an airborne concentration of 15,302 ppm for 10 minutes caused oxidative stress in the cerebellum, cerebral cortex, and brainstem (Kakkar et al, 1992).

Physicochemical

Physical Characteristics

    A) Aniline is a highly toxic, clear, oily liquid, which turns brown with exposure to air and light. It has a distinctive, amine-like, or musty, fishy odor and an acrid, burning taste. It is heavier than water and its vapors are heavier than air; the fumes are poisonous if inhaled. It is combustible, and volatile with steam (AAR, 2000; (ACGIH, 1991; Budavari, 2000; Lewis, 2000; Lewis, 1998).

Ph

    A) 8.1 (for a 0.2 mol aqueous solution) (Budavari, 2000)

Molecular Weight

    A) 93.13

Other

    A) ODOR THRESHOLD
    1) 0.5 ppm (CHRIS , 2001; OHM/TADS, 2001)
    2) MEDIUM ODOR THRESHOLD : 70.1 ppm (OHM/TADS, 2001)
    3) UPPER ODOR THRESHOLD: 128 ppm (OHM/TADS, 2001)

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